Diagnostic method



A ril 26, 1966 e. B. COOK DIAGNOSTIC METHOD Filed May 29, 1961 United States Patent 3,247,841 DTAGNUSTIQ METHOD Galen B. Cook, 1027 Commodore, Richmond Heights, Mo.

Filed May 29, 1961, Ser. No. 113,413 12 Claims. (Cl. 128-2) This invention relates to the detection and analysis of abnormalities, particularly small abnormalities in the surfaces defining internal cavities in living animals. It has particular application to the human large intestine, and Will be described in connection therewith, but its usefulness is not confined thereto.

The need for a reliable and discerning method for examining the interior of the large intestine can be apreciated by reviewing the diverse and inventive approaches which have evolved in the history of colon diagnosis: radiography of the colon began with the radiopaque enema; this was followed by the doublecontrast enema, the use of semi-transparent media, the addition of over-exposed roentgenographic films and highvoltage technique. Subsequently, chemicals such as tannic acid and isatin were added to the barium sulfate, and later external bag compression, filling of the urinary bladder, the Chassard-Lapine and cephalad-oblique-prone projections were introduced. Proctosigmoidoscopy was begun with the proctosigmoidoscope and extended by lengthening the barrel, by coloscopy through colotomies, by using the traction sigmoidoscope, the suction-lavage sigmoidoscope, the Lucite Y tube, and, most recently, the flexible coloscope. The third avenue of approach has been cytologic study of material by bulb pipetting, sigmoidoscopic aspiration, enema washing, direct tissue smearing, and millipore filtration of colonic washings.

From this array of techniques useful combinations have emerged and are applied today regularly. The reliability of any combination however is not absolute, nor is the applicability universal for the discovery of small sessile cancers of the large intestine-especially when they are located in the region of the sigmoid colon. A recent evaluation of the accuracy of cytologic study of material collected above the reach of the sigmoidoscope reported only 4.3% reliability. Even with sigmoidoscopes of advanced design the sigmoid colons of percent of patients could not be satisfactorily examined because of anatomical peculiarities. Coloscopy is attended by an appreciable risk of secondary wound infection and is not satisfactory for the examination of the colonic flexures. The accuracy of the barium enema, with all of its modifications, has seldom exceeded 90 percent; in fact reliabilities as low as 28 percent have been reported.

One of the objects of this invention is to provide a method for accurately locating and analyzing abnormalities within an internal cavity of a living animal with greater accuracy and less danger, difiiculty and expense than methods known heretofore.

Still another object is to provide a method for diagnosis of abnormalities in internal cavities of living animals to result in a substantially permanent record.

Other objects will become apparent to those skilled in the art in the light of the following description and accompanying drawing.

In accordance with this invention, generally stated, a method of diagnosis is provided wherein there is introduced into an internal cavity of a living animal a nontoxic fluent material capable of being set at a temperature compatible with cell viability, preferably body temperature, to a surface-conforming, coherent, unplastic, pliant condition, with a sufiiciently fine-grained surface to reproduce for diagnosis the physical features of abnormalities sought to be detected. Preferably, the fluent material contains a radiopaque substance, and the course of the liquid being introduced may be followed radiologically. When the liquid has been introduced to the desired position, it is set in situ. Again, preferably, an intumescant is activated during the setting process, to ensure that the surface of the set material is in snug but physiologically harmless engagement with the surfaces defining the cavity, and to produce a spongy, soft mass.

The set material is then caused to be removed from the cavity. In the case of the colon, preferably the set material is evacuated by defecation.

In the interests of accuracy, it is important, particularly in the diagnosis of abnormalities in the large intestine, that the cavity be purged of excrement. In the case of the colon, a simple enema has been found entirely satisfactory. Also in the case of the large intestine, it has been found desirable, though not absolutely essential, to maintain the area below the superior valve of the rectum free of set material, as by a small inflatable bladder, surrounding the tube by which fluent material is introduced.

Preferably, the fluent material consists of a liquid elastomeric substance, vulcanizing or polymerizing agent, an intumescant, and a radiopaque material. Not all of these elements need be included. It is necessary, however, that the composition be sufliciently fluent to be readily introduceable into the cavity; that it be capable of being converted to a surface-conforming, coherent, unplastic, pliant, soft form at body temperature or near to it; and that it be nontoxic in both its fluent and solid states. Preferably, it is a liquid with low initial viscosity, miscible with radiopaque media. It should be converted from liquid to solid rapidly and predictably within narrow limits, and preferably, endothermically. If the setting, crosslinking or vulcanizing process is exothermic, the temperature rise must be very small. The solid material should be freely and atraumically separable from mucous membrane, or any other body surface under study.

It has been found that, particularly with the preferred embodiment of composition, described hereafter, excellent control is possible, the material polymerizes (actually it is believed to crosslink) to a satisfactory solid state in the body within about ten minutes of its introduction, the resultant spongy mass is readily and painlessly evacuated, the surface of the model produced faithfully reflects the abnormalities of the mucosal surface, and suflicient numbers of the cells from the surfaces of the abnormalities adhere to the model to make the analysis and diagnosis of the abnormalities more certain than methods known heretofore.

In the drawing, FIGURE 1 is a diagrammatic View of a human large intestine, partly cut away, showing a tube being inserted per anus;

FIGURE 2 is an enlarged detail sectional view showing liquid being introduced to the sigmoid colon of FIG- URE 1; and

FIGURE 3 is a view in back elevation of a model produced in accordance with the method of the invention, exhibiting the imprint of an abnormality shown in FIG- URE 1.

In the development of the method of this invention, various materials have been used. The first to be tried, was a Thiokol rubber, a condensation polymer of ethylene chloride and sodium tetra sulfide. This material was used successfully in dogs, which have straight colons, but

it is too stifl for satisfactory use in human large intestines. Gelatin-egg White compositions (10-30 parts by volume of stifliy foamed egg whites, -70 parts bovine gelatin) have also been tried. While they produce a sufliciently pliable model, the model is too fragile (not sufficiently coherent) to be satisfactory. The compositions set forth in the following examples are, with any limitations set forth in an example, eminently satisfactory. However, so far as the method is concerned, it can be appreciated that numerous other materials already commercially available, and others which will become commercially available hereafter, are or will be suitable for the practice of the method, once the method is disclosed.

Example 1 Parts by I weight Room temperature vulcanizing silicone rubber (Silastic RTV 502), a liquid prepolymer dimethyl sili- The viscosity of the material, immediately after the catalyst is added, and before setting begins appreciably, is less than 6,000 centistokes.

The method, with the composition of Example 1 as an example, is as follows. The composition of Example 1 was made up, the catalyst being added immediately before the material was used. The material was put into a polyethylene container in a commercial sealant gun connected to a rubber tube with an internal diameter of 7 millimeters. The gun delivered the mixture at a pressure of about pounds per square inch. The tube was 25 centimeters long. The patient was positioned so as to permit the flow of liquid to be observed radiographically, the tube was inserted in the colon, per anus, and the liquid introduced. The silicone rubber foam was caused to intumesce and both the foaming and nonfoaming silicone rubber were caused to set by the catalyst within a few minutes of the liquids introduction into the colon. The set model was evacuated by the normal defecatory process of the patient. Cellular material was then removed from the model, and the model studied for imprint detail. It has been found that imprints of abnormalities such as carcinomas and adenomatous polyps are reproduced with excellent clarity. The model faithfully resumes the shape in which it was formed, so that the location of the abnormality can be established with the greatest nicety. In numerous tests of the method conducted on surgical specimens of the sigmoid colon containing adenocarcinomas, small malignancies, which had remained occult in conventional observation, were discovered by a study of the model produced by the method of this invention.

Cells may be removed from the model in various ways, as by forceps or by scraping. Dr. Alexander Margulis has suggested that the model be' suspended and agitated in Hartmans (lactatedRingers) solution. This method of cell removal gives excellent results. When the specimen or model is removed from the Hartmans (lactated Ringers) solution, the cellular suspensions in the solution are centrifuged and examined microscopically. The cytological examination of the cellular debris from the model in every malignant lesion, was positive for carcinomatous cells.

The drawing illustrates steps in the method in its preferred form. In the embodiment, a plastic bag 1 contains a settable liquid and a rupturable container of catalyst 2. The bag 1 is connected to a tube-3, at the free end of which, and surrounding the tube, is a bladder 4. The tube 3 preferably has an internal diameter between 5 and 20 millimeters. The bladder 4 is sealed and is connected, by means of an air tube 5, to a bulb 6, filled with sufficient gas to expand the bladder 4. A clamp 7 closes the air tube 5.

As shown in FIGURE 1, the end of the tube 3 isinserted into the rectum. The clamp 7 is released and the bulb 6 collapsed to inflate the bladder 4. The clamp is then tightened again to maintain the bladder inflated.

The container 2 is ruptured and the catalyst quickly mixed with the liquid. The catalyzed liquid isthen forced into the colon, as shown in FIGURE 2. The amount of liquid introduced depends upon the length of large intestine to be surveyed. The liquid then intumesces and sets to form a model 9. When the model 9 is set, the clamp 7 is released to permit the bladder 4 to collapse, and the tube and bladder are withdrawn. The model is then caused to be evacuated. As illustrated in FIGURES l and 3, an abnormality 8 in the wall of the colon appears as an imprint 10 in the model. The usefulness of the bladder 4 can be appreciated by an examination of FIGURES 1 and 2.

The method is substantially the same with any of the compositions of the examples, and will be with any compositions exhibiting the desired characteristics. The following examples are merely illustrative of suitable compositions.

Example 2 Parts by weight Room temperature vulcanizing silicone rubber (Silastic RTV 502), a liquid prepolymer dimethyl silicone, about 45,000 cs. Silicone rubber foam (Silastic Q-3-0030), intumescant, about 5,000 cs. Cyclic dimethyl polysiloxane (silicone fluid), 20 centistokes 2 Diatrizoate sodium (in 20 parts water), radiopaque material 25 The viscosity of the material, immediately after the catalyst is added, and before setting begins appreciably, is less than 6,000 centistokes.

Example 3 The following ranges of the silicone ingredients of Examples 1 and 2 have been found operative. Other proportions may be useful, but have not been actually tried.

In any of Examples 1, 2 and 3, other room temperature vulcanizing (RTV) silicone rubbers and silicone fluids may be used. The Silastic products are obtainable from Dow Chemical Co. Operative RTV silicone rubber corresponding to Silastic RTV 502 and Q30030 are obtainable from General Electric, designated RTV 11 and RTV 40, and RTV and respectively. These latter are also curable with stannous octoate. Other metal soap catalysts, such as tin dilaurate, iron octoate, and chromium octoate may be used, but they are slower acting, hence not as satisfactory for the purpose in this respect.

Example 4 Parts by weight Polysulfide liquid polymer, Thiokol LP2 (Thiokol Chemical Corporation) 70 Dipolymer oil (plasticizer, thinning agent) l0 Cumene hydro peroxide (70%) 8 3-diethylaminopropylamine 2 The polysulfide liquid polymers (polymers of his (ethylene oxy) methane containing disulfide linkages) show promise as useful compounds for the method of this invention. They set at room temperature, and admit of the use of numerous curing agents, activators and plasticizers (cf. Bulletin entitled LP-2 Polysulfide Liquid Polymer, of Thiokol Chemical Corporation, id. l-61H).

Example 5 Mols Adipic acid 16 Diethylene glycol 16 Trimethyl propane 1 Tolylene diisocyanate Parts by weight Adipic acid ester of N-diethylaminoethanol 3 Ammonium oleate 1 Sulfonated castor oil 1.5 Water 1.5 Paraffin oil 0.5

One hundred parts, by volume, of A, forty-seven parts, by volume of B, and ten parts, by volume, of C are mechanically stirred and the mixture quickly introduced. This produces a flexible foamed polyurethane model. For a less dense material, less diisocyanate is used. Such foamed polyurethanes show great promise in vitro. They have not been completely tested in vivo.

Numerous variations, within the scope of the appended claims, in the method of this invention will occur to those skilled in the art in the light of the foregoing disclosure.

For example, any other suitable radiopaque material, compatible with the elastomeric model forming liquid, may be used, such as sodium acetrizoate, sodium diprotrizoate, diatrizoate methyl glucamine, ethyl iodophenylundecylate and barium sulfate. Other catalysts, such as have been suggested above, may be used in conjunction with the silicone rubber liquids, and, of course, other catalysts or vulcanizers may be used with other elastomeric materials.

Other likely elastorneric or model-forming liquids such as amylose starches, may, as has been suggested, he used.

While the preferred viscosity has been given merely as below 10,000, the viscosity may be, and preferably is much lower.

In the method, when only a limited length of colon is to be examined, for example, so that there is no danger of introducing an excessive amount of material, or when the capacity of the internal cavity is known, his not necessary to use the radiologic control, so that no radiopaque material need be incorporated into the mold-forming liquid.

In the case of an internal cavity from which a mold can easily be removed, it may not be necessary to use an intumescant material. However, the intumescant not only provides a spongy core, but, in swelling, provides a snug, though physiologically harmless engagement with the cavity-defining surface, giving a sharply defined impress to the mold.

The use of the viscosity-reducing ingredient is a matter of ease of insertion of the liquid, the pliability of the set material being substantially unaffected thereby.

The terms fluent, coherent, unplastic, pliant, intumesce or intumescant, and nontoxic have been used in the specification and claims in the following senses: fluent is used to meanflowable sufficiently to be introduced rapidly and atraumatically into the cavity to be tested; coherent is used to mean that the molded shape hangs together sufiiciently to be removed intact, or, in extreme constrictive cases, in large sections; unplastic is used to mean that the set material is not subject to permanent deformation under the forces applied in the removal of the shape; pliant is used to mean sufiiciently soft to permit atraumatic removal of the molded shape, as by the normal defecatory process from the colon; and intumesce is used to mean to swell; preferably by bubbling, to form a soft but snug-fitting shape. Intumescant is used to mean the swelling agent or the characteristic of swelling. Nontoxic is used to mean that the material (both fluent and set) is substantially harmless as employed in the method of this invention for the duration of time required. Thus, for example, certain of the ingredients per se may be toxic, but used in the particular cavity (e.g. colon), in the concentrations and for the lin1- ited time required, have'no substantial toxic effect.

Having thus described the invention, what is claimed and desired to be secured by Letters Patent is:

11. A method of diagnosis comprising purging the colon of a patient; filling at least a portion of the colon by rectally administering a liquid comprising room temperature vulcanizing silicone rubber, intumescant, vulcanizer and suflicient low viscosity cyclic dimethyl siloxane to produce an effective viscosity of less than 10,000 centistokes; causing said liquid to intumesce and set, and re moving said set material from the colon by defecation.

2. The process of diagnosing the nature, form and location of an abnormality in the wall of the colon of a living person, comprising filling, per anus, that portion of the colon at and posterior to the area in which the abnormality is, with a mixture of a setting agent and a liquid elastomeric material which sets, in the presence of said setting agent, at or below about body temperature to a surface conforming, coherent, unplastic, pliant solid with a surface more fine grained than said abnormality; setting said material in situ while maintaining said material in intimate contact with said abnormality, and removing the set material per anus from the colon.

3. The process of diagnosing the nature, form and location of an abnormality in the wall of the colon of a living person, comprising blocking at least a portion of the rectum to passage of liquid from the colon; while maintaining the said blocking, filling, per anus, that portion of the colon at and posterior to the area in which the abnormality is, with a mixture of a setting agent and a liquid elastomeric material which sets, in the presence of said setting agent, at or below about body temperature to a surface conforming, coherent, unplastic, pliant solid with a surface more fine grained than said abnormality; setting said material in situ while maintaining said material in intimate contact with said abnormality and while maintaining said blocking; unblocking the rectum, and removing the set material from the colon.

4. The process of diagnosing the nature, form and location of an abnormality in the Wall of the colon of a living person, comprising filling, per anus, that portion of the colon at and posterior to the area in which the abnormality is, with a mixture of setting agent and a liquid elastomeric material which sets, in the presence of said setting agent, at or below about body temperature to a surface conforming, coherent, unplastic, pliant solid with a surface more fine grained than said abnormality; setting said material in situ while maintaining said material in intimate contact with said abnormality; trapping on the surface of said set material cells from the said abnormality, and removing the set material per anus from the colon.

5. The process of diagnosing the nature, form and location of an abnormality in the wall of the colon of a living person, comprising filling, per arms, that portion of the colon at and posterior to the area in which the abnormality is, with a mixture of a setting agent and a liquid elastomeric material, containingg a radiopaque substance,

. which sets, in the presence of said setting agent, at or below about body temperature to a surface conforming, coherent, unplastic, pliant solid with a surface more fine grained than said abnormality; locating the material radiologically; setting said material in situ while maintaining said material in intimate contact with said abnormality, and removing the set material per anus from the colon.

6. The process of diagnosing the nature, form and location of an abnormality in the wall of the colon of a living person, comprising filling, per anus, that portion of said material to intumesce and concurrently setting said material in situ while maintaining said material in intimate contact with said abnormality, and removing the set material per anus from the colon.

7. The method of diagnosing the nature, form and location of an abnormality in the wall of the colon of a living person, comprising filling at least the portion of the colon in which the abnormality is by administering per anus a liquid comprising room temperature vulcanizing silicone rubber, 'intumescant, vulcanizer and sufficient low viscosity cyclic dimethyl siloxane to produce an effective viscosity of less than 10,000 centistokes; causing said liquid to intumsce and set, and removing said set material.

8. The method of diagnosing the nature, form and location of an abnormality in the wall of the colon of a living person, comprising filling at least the portion of the colon in which the abnormality is by administering per anus a liquid comprising room temperature vulcanizing silicone rubber, intumescant, vulcanizer and sufficient low viscosity cyclic dimethyl siloxane to produce an effective viscosity of less than 10,000 centistokes while blocking at least a portion of the rectum against filling by said liquid; causing said liquid to intumesce and set in the colon, while continuing the blocking of the rectum; removing said blocking and removing said set material per anus.

9. The process of diagnosing the nature, form and location of an abnormality in the wall defining an externally opening internal cavity in a living animal, comprising filling the part of said cavity including the said abnormality, with a mixture of a setting agent and a liquid elastomeric material which sets, in the presence of said setting agent, at or below about the body temperature of said animal to a surface conforming, coherent, unplastic, pliant solid with a surface more fine grained than the said abnormality; setting said material in situ while maintaining the said material in intimate contact with said abnormality, capturing, upon the surface of said set material, cells from said abnormality, and removing the set material from the cavity through said external opening.

10. The process of diagnosing the nature, form and location of an abnormality in the wall defining an externally opening internal cavity in a living animal, comprising filling the part of said cavity including the said abnormality, with a mixture of a setting agent and a liquid elastomeric material which sets, in the presence of said setting agent, at or below about the body temperature of said animal, to a surface conforming, coherent, unplastic, pliant solid with a surface more fine grained than the said abnormality; causing said material to intumesce and concurrently setting said material in situ while maintaining the said material in intimate contact with said abnormality; capturing, upon the surface of said set material, cells from said abnormality, and removing the set material from the cavity through said external opening.

11. The process of diagnosis comprising mixing together a setting agent and a liquid elastomeric substance capable of changing state in the presence of said setting agent at a temperature compatible with cell viability to a solid, surface conforming, coherent, unplastic, pliant condition, with a sufficiently fine-grained surface to exhibit for diagnosis an imprint of the physical features of abnormalities sought to be detected; subsequently, before said substance has solidified, introducing said liquid mixture into an internal cavity of a living animal; permitting said substance to change state while causing said substance to intumesce sufiiciently to form a snug but physiologically harmless engagement of the solidifying substance with the internal cavity-defining surfaces, and, after the substance has solidified, removing the solidified material from said cavity.

12. The process of diagnosis comprising mixing together a setting agent and a liquid elastomeric substance capable of changing state in the presenceof said setting agent at a temperature compatible with cell viability to a solid, surface conforming, coherent, unplastic, pliant condition, with a sufiiciently fine-grained surface to exhibit for diagnosis an imprint of the physical features of an abnormality sought to be detected; subsequently, before said liquid substance has changed state, introducing said mixture into an internal cavity of a living animal; permitting the substance to change state while causing said substance to intumesce sufficiently to form a snug but physiologically harmless engagement of the solidifying substance with the internal cavity defining surfaces; capturing upon the surface of said substance, as it changes state to solid form, cells from said surfaces; removing the solidified substance from said cavity; removing said cells from the surface of said solidified substance, and examining the cells.

References Cited by the Examiner UNITED STATES PATENTS 2,155,658 4/1939 Herrmann 167-95 X 2,190,384 2/1940 Newman 128-400 2,311,158 2/1943 Conway 32-17 35 2,475,802 7/1949 Osserman 18-55.05 2,613,398 10/1952 Crowell 18-5505 2,701,559 2/1955 Cooper 128-2 2,712,160 7/1955 Sterczek 18-55.02 2,727,278 12/ 1955 Thompson 18-59 2,744,521 5/1956 Schmid 128-2 2,764,565 9/ 1956 Hoppe 260-2.5 2,773,502 12/1956 Kaslow 167-95 X 2,832,722 4/1958 Singher 167-95 2,833,732 5/1958 Weyer 260-42 45 2,853,424 9/1958 Priewe 167-95 2,877,212 3/1959 Seligman 260-2.5 2,970,945 2/1961 Free 167-84.5 2,996,433 8/1961 Hoppe 167-95 3,003,496 10/1961 Klein 128-2 3,037,495 6/1962 Naz 128-2 3,037,496 6/1962 Melges 128-2 3,070,555 12/ 1962 Bruner 260-42 OTHER REFERENCES Thiokol Liquid Polymer LP-2, received Feb. 24, 1948,

18 pp., mimeographed booklet TS-1925 T 48, Thiokol Publications, Thiokol Chem. Corp., Trenton, NJ. 7

Booklet 2-59 received Mar. 12, 1959 (Fillers for Polysulfide Liquid Polymers) 8 page printed booklet, Thiokol Publications, Thiokol Chem. Corp., Trenton, NJ.

The Bulletin, Dow Corning, Midland, Michigan, vol. 2, No.2, April 1960, page 8.

Brown, Annals of Surg., vol. 152, No. 3, September 1960, pp. 534-537, RD 1, A61.

65 RICHARD A. GAUDET, Primary Examiner.

R. I. HOFFMAN, JORDAN FRANKLIN, Examiners. 

1. A METHOD OF DIAGNOSIS COMPRISING PURGING THE COLON OF A PATIENT; FILLING AT LEAST A PORTION OF THE COLON BY RECTALLY ADMINISTERING A LIQUID COMPRISING ROOM TEMPERATURE VALCANIZING SILICONE RUBBER, INTUMESCANT, VULCANIZER AND SUFFICIENT LOW VISCOSITY CYCLIC DIMETHYL SILOXANE TO 